Department of Veterinary Disease Biology, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Bagsvaerd, Denmark.
Haemophilia. 2013 Nov;19(6):913-9. doi: 10.1111/hae.12198. Epub 2013 Jun 4.
Prophylaxis in severe haemophilia significantly increases health-related quality of life for patients, but the dosing frequency still constitutes a challenge. Thus, there is a need for new treatment options, utilizing compounds with longer duration of action, while still maintaining potency. The objective of this study was to evaluate the acute and prolonged effects of a new glycoPEGylated recombinant factor VIII (rFVIII) (N8-GP) in a venous bleeding model in haemophilia A mice and to compare the efficacy and potency to turoctocog alfa (rFVIII). Following intravenous administration of turoctocog alfa or N8-GP to normal and FVIII-deficient mice, bleeding time and blood loss from a saphenous vein incision were evaluated in an acute dose-response study and a duration of action study. In the acute setting, N8-GP dose dependently reduced the number and duration of bleeding episodes as well as blood loss compared to FVIII-deficient mice, reaching statistical significance at doses as low as 5-10 U kg(-1) . In the duration of action study, a significantly prolonged and maintained effect of N8-GP was found for up to 48 h after dosing, whereas the effect of rFVIII was no longer present for any end-points 24 h after dosing. Seventy-two hours after dosing, no significant effect of either compound was found. This study shows a prolonged haemostatic effect of N8-GP compared to rFVIII supporting other recent studies that N8-GP may hold a potential to increase the quality of life for patients with haemophilia A by reducing dosing frequency.
预防重度血友病可显著提高患者的健康相关生活质量，但给药频率仍然是一个挑战。因此，需要新的治疗选择，利用作用时间更长的化合物，同时保持效力。本研究的目的是评估新型糖基化聚乙二醇化重组因子 VIII（rFVIII）（N8-GP）在血友病 A 小鼠静脉出血模型中的急性和长期效果，并比较其疗效和效力与 turoctocog alfa（rFVIII）。在静脉给予 turoctocog alfa 或 N8-GP 后，在急性剂量反应研究和作用持续时间研究中评估正常和 FVIII 缺乏型小鼠的出血时间和隐静脉切开术的失血量。在急性环境中，与 FVIII 缺乏型小鼠相比，N8-GP 剂量依赖性地减少了出血发作的次数和持续时间以及失血量，在 5-10 U kg(-1) 的剂量下达到统计学意义。在作用持续时间研究中，发现 N8-GP 的作用可显著延长并维持长达 48 小时，而 rFVIII 的作用在给药后 24 小时的任何终点均不再存在。给药后 72 小时，未发现两种化合物有明显的作用。这项研究显示 N8-GP 的止血效果比 rFVIII 更长，支持其他最近的研究表明，N8-GP 可能通过减少给药频率来提高血友病 A 患者的生活质量。
